Local Proinflammatory Effects of Repeated Skin Exposure to Warfarin, An Anticoagulant Rodenticide in Rats

Objective： To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin. Methods： Rats were exposed to warfarin by applying 10 μg of warfarin‐sodium to 10‐12 cm 2 skin （range 0.8‐1 μg per 1 cm 2 ） for 3 consecutive days. Tissue injury was evaluated by lipid peroxidation, histomorphological changes and signs of reparative activity in skin. T cell infiltration and selected aspects of epidermal cell activity were examined as indicators of immune/inflammatory skin response to warfarin application. Results： Repeated warfarin application exerted no effect on skin metabolic viability, but resulted in tissue injury （increased malondialdehyde, MDA, production, evident histo‐morphological changes in epidermis and dermis depicting cell injury and death）. Increased numbers of proliferating cell nuclear antigen （PCNA ＋ ） cells indicated reparative processes in injured skin. Infiltration of CD3 ＋ cells （T lymphocytes） along with the increased production of tumor necrosis factor‐α （TNF‐α） by epidermal cells from warfarin‐treated skin and their co‐stimulatory effect in an in vitro T‐cell activation assay demonstrated immunomodulatory effects of epicutaneous warfarin. Conclusion： Presented data have documented tissue damage associated with immune/ inflammatory activity in skin exposed to warfarin. Observed effects are relevant to immunotoxic potential of this anticoagulant in settings of external exposure.

Gender Differences in Acute Cadmium-Induced Systemic Inflammation in Rats

Objective To examine the presence of gender differences in pro-inflammatory potential of cadmium in rats by comparing systemic inflammatory response to acute cadmium intoxication in animals of the two sexes. Methods Basic aspects of this response were evaluated, including plasma levels of inflammatory cytokines tumor necrosis factor （TNF） and interleukin-6 （IL-6） and of major rat acute phase protein alpha 2-macroglobulin （alpba2-M）, as soluble indicators of inflammation, and the number and activity of peripheral blood leukocytes, as cellular indicators of inflammation. Results Differential increases of IL-6 and alpha 2-M （higher in males than in females） in peripheral blood cell counts and types （leukocytosis and shift in the ratio of granulocytes to lymphocytes more pronounced in males vs females） and in levels of neutrophil priming （higher in males vs females） were noted. Conclusion The data document a more intense inflammatory response to cadmium administration in males. The sex differences in inflammatory effects of cadmium might be taken into consideration in studying the toxicity of this heavy metal.

Gender Differences in Pulmonary Inflammation Following Systemic Cadmium Administration in Rats

Objective To examine the presence of gender differences in pulmonary inflammation evoked by acute systemic cadmium administration in rats. Methods Presence of basic indicators of lung inflammation （inflammatory cytokine lung content, leukocyte infiltration and activity of cells recovered from lungs by enzyme digestion） was analyzed and compared in animals of the two sexes. Results Intraperitoneal administration of cadmium （1.0 mg/kg） resulted in higher cadmium content in lungs of female rats. Higher tumor necrosis factor （TNF） content was noted in lung homogenates of male rats, while interleukin-6 （IL-6） content was slightly, but signifaicantly greater in lungs of female rats. Increased leukocyte infiltration was observed in lungs of male rats, mainly due to neutrophils. Increased responsiveness to phorbol myristate acetate （PMA） stimulation was noted in cells recovered from lungs of male rats. Rise in intracellular content of myeloperoxidase （MPO） was noted in lung cells from cadmium-treated rats of both sexes, but higher in cells from male rats. Conclusion Presented data documented a more intense pulmonary inflammatory response to systemic cadmium administration in males, with higher IL-6 levels in lungs of female individuals. These sex differences in proinflamatory activity of cadmium in lungs should be taken into consideration in studying the remote toxicity of this heavy metal.

Oral Cadmium Intake Enhances Contact Allergen-induced Skin Reaction in Rats

Objective The effect of oral cadmium(Cd)intake to influence contact skin allergies was examined,since it is known that Cd is a heavy metal that affects many tissues,including the skin,in which it disturbs homeostasis,thus resulting in inflammation and injury.Methods Male rats were evoked with experimental contact hypersensitivity reaction(CHS)to hapten dinitrochlorobenzene(DNCB),after prolonged(30 day)oral exposure to an environmentally relevant Cd dose(5 ppm).The ear cell population was analyzed with flow cytometry.Cytokine production by ear skin cells and the activity of skin-draining lymph node(DLN)cells were measured using enzyme-linked immunosorbent assay(ELISA).Results Orally acquired Cd(5 ppm)increased CHS intensity only in Dark Agouti(DA)rats by affecting inflammatory responses in both the sensitization(an increase of IFN-γ and IL-17 cytokine production)and challenge(an increase of CD8^(+)and CD4^(+)cell number and TNF,IFN-γ and IL-17 cytokine production)phases.An increased CHS reaction was seen in Albino Oxford(AO)rats only at a high Cd dose(50 ppm),during the challenge phase(an increase of CD8^(+)and CD4^(+)cell number and TNF,IFN-γ and IL-17 cytokine production).Conclusion These novel data indicate that oral Cd intensifies the skin response to sensitizing chemicals such as DNCB.

Physiological strategies in wild rodents:immune defenses of commensal rats

The importance of issues associated with urban/commensal rats and mice(property damage,management costs,and health risks)press upon research on these animals.While the demography of commensal rodents is mostly studied,the need for understanding factors influencing their natural morbidity/mortality is also stressed.In this respect,more attention is expected to be paid to immunity,the physiological mechanism of defense against host survival threats(pathogens,parasites,diseases).Commensal rats and mice carry numerous pathogens that evoke diverse immune responses.The state of immunity in commensal house mice is studied in great detail,owing to the use of laboratory strains in biomedical research.Because commensal rats are,compared to mice,carriers of more zoonotic agents,rats’immunity is studied mainly in that context.Some of these zoonotic agents cause chronic,asymptomatic infections,which justified studies of immunological mechanisms of pathogen tolerance versus clearance regulation in rats.Occurrence of some infections in specific tissues/organs pressed upon analysis of local/regional immune responses and/or immunopathology.A survey of immunological activity/responses in commensal rats is given in this review,with mention of existing data in commensal mice.It should throw some light on the factors relevant to their morbidity and lifespan,supplementing the knowledge of commensal rodent ecology.

Immune defense of wild-caught Norway rats is characterized by increased levels of basal activity but reduced capability to respond to further immune stimulation

Studies of wild animals’immunity often use comparison with laboratory-raised individuals.Using such an approach,various data were obtained concerning wild Norway rat’s immunity.Lower or higher potential of immune system cells to respond to activation stimuli were shown,because of analysis of disparate parameters and/or small number of analyzed individuals.Inconsistent differences between laboratory and wild rats were shown too,owing to great response variability in wild rats.We hypothesized that wild rats will express more intense immune activity compared to their laboratory counterparts which live in a less demanding environment.To test this,we analyzed the circulating levels of inflammatory cytokine interleukin-6(IL-6),a mediator which has a central role in host immune defense.In addition,we examined the activity of the central immune organ,the spleen,including cell proliferation and production of pro-inflammatory cytokines interferon-γ(IFN-γ)and interleukin-17(IL-17),which are major effectors of cellular adaptive immune response.In order to obtain reasonable insight into the immunity of wild Norway rats,analysis was conducted on a much larger number of individuals compared to other studies.Higher levels of plasma IL-6,higher spleen mass,cellularity and basal IFN-γproduction concomitantly with lower basal production of anti-inflammatory cytokine interleukin-10(IL-10)revealed more intense immune activity in the wild compared to laboratory rats.However,lower responsiveness of their spleen cells’proinflammatory cytokine production to concanavalin A(ConA)stimulation,along with preserved capacity of IL-10 response,might be perceived as an indication of wild rats’reduced capability to cope with incoming environmental stimuli,but also as a means to limit tissue damage.